蛋白质SUMO化修饰

PROTEINMODIFICATIONBYSUMOEricaS.JohnsonDepartmentofBiochemistryandMolecularPharmacology,ThomasJeffersonUniversity,Philadelphia,Pennsylvania19107;email:[e-mail]-translationalmodification,ubiquitin-likeprotein,PIAS,Ubc9,UlpfAbstractSmallubiquitin-relatedmodifier(SUMO)familyproteinsfunctionbybecomingcovalentlyattachedtootherproteinsaspost-translationalmodifications.SUMOmodifiesmanyproteinsthatparticipateindiversecellularprocesses,includ-ingtranscriptionalregulation,nucleartransport,maintenanceofgenomeintegrity,andsignaltransduction.ReversibleattachmentofSUMOiscontrolledbyanenzymepathwaythatisanalogoustotheubiquitinpathway.ThefunctionalconsequencesofSUMOattachmentvarygreatlyfromsubstratetosubstrate,andinmanycasesarenotunderstoodatthemolecularlevel.FrequentlySUMOaltersinteractionsofsubstrateswithotherproteinsorwithDNA,butSUMOcanalsoactbyblockingubiquitinattachmentsites.AnunusualfeatureofSUMOmodificationisthat,formostsubstrates,onlyasmallfractionofthesubstrateissumoylatedatanygiventime.ThisreviewdiscussesourcurrentunderstandingofhowSUMOconjugationiscontrolled,aswellastherolesofSUMOinanumberofbiologicalprocesses.CONTENTSINTRODUCTION........................................356THESUMOCONJUGATIONPATHWAY........................357SUMO.............................................358SUMO-ActivatingEnzyme(E1)..............................360SUMO-ConjugatingEnzyme(E2).............................361SUMOLigases(E3s)....................................361SUMO-CleavingEnzymes.................................364SubstrateSpecificityinSumoylation...........................365RegulationofSUMOConjugation.............................365BIOLOGICALFUNCTIONSOFSUMO..........................366Transcription..........................................367PMLNuclearBodies.....................................368ChromosomeOrganizationandFunction.........................370DNARepair..........................................371NuclearTransport.......................................372SumoylationofNonnuclearProteins...........................373SignalTransductionPathways...............................373Annu.Rev.Biochem.2004.73:355–82doi:10.1146/annurev.biochem.73.011303.074118Copyright©2004byAnnualReviews.AllrightsreservedFirstpublishedonlineasaReviewinAdvanceonMarch5,20043550066-4154/04/0707-0355$14.00Annu.Rev.Biochem.2004.73:355-382.Downloadedfrom’sInteractionsWiththeUb-ProteasomePathway...............374SumoylationModulatesInteractionsofSubstrate....................375StoichiometricVersusCyclingRolesforSUMOConjugation............376CONCLUDINGREMARKS.................................377INTRODUCTIONCovalentmodificationsofproteinsarerapid,energeticallyinexpensivemecha-nismsforreversiblyalteringproteinfunction,andmodificationssuchasphos-phorylation,acetylation,andubiquitylationparticipateinmostcellularactivities.Ubiquitylation,whichinvolvesattachmentofthe76-residueproteinubiquitin(Ub)tootherproteins,oftentargetsthesubstrateproteinfordegradationbytheproteasome,butitcanalsohaveseveralotherfunctions(1,2).Recently,severalsmallubiquitin-likeproteins(Ubls)thatalsoactaspost-translationalmodifica-tionsonotherproteinshavebeendiscovered.TheseUblsvarywidelyintheirdegreeofsequencesimilaritytoUbbutshareacommonchemistryforbecomingattachedtointernallysineresiduesinsubstrateproteins(3).Ublshaveavarietyofdifferentfunctions,buttheydonottargettheirsubstratesdirectlyforprotea-some-dependentproteolysis.TheUblswiththewidestrangeoffunctionsandthemostknownsubstratesarethemembersoftheSUMO(smallubiquitin-relatedmodifier)family.SeveralpreviousreviewsonSUMOcoverearlierworkandspecifictopicsindepth(4–8).SUMOsconstituteahighlyconservedproteinfamilyfoundinalleukaryotesandarerequiredforviabilityofmosteukaryoticcells,includingbuddingyeast,nematodes,fruitflies,andvertebratecellsinculture(9–13).Inmulticellularorganisms,SUMOconjugationtakesplaceinalltissuesatalldevelopmentalstages(14–21).Sinceitsdiscoveryin1996,SUMOhasbeenfoundcovalentlyattachedtomorethan50proteins,whichincludetheandrogenreceptor,I
B,c-jun,histonedeacetylases(HDACs),p53,andotherproteinsthatparticipateintranscription,DNArepair,nucleartransport,signaltransduction,andthecellcycle.MostSUMO-modifiedproteinsthathavebeencharacterizedinmamma-liansystemsareinvolvedintranscription,whichisoftenrepressedbySUMOconjugation.However,geneticstudiesinmodelorganismshavepointedtoaroleforSUMOinchromosomedynamicsandhigherorderchromatinstructures,illustratingthediversityofSUMOfunction.Atthistime,onlyonefairlyuninformativegeneralizationaboutthedown-streamconsequencesofSUMOattachmentispossible:SUMOalterssubstrateinteractionswithothermacromolecules.SUMOoftenhasapositiveeffectonprotein-proteininteractions,anditpromotesassemblyofseveralmulti-proteincomplexes.However,theeffectsofSUMOoninteractionsvaryfordifferentsubstrates.Forexample,sumoylationallowsRanGAP1tobindtightlytothenuclea